Various scientific and scholarly articles are referred to in brackets and footnotes throughout the specification. These articles are incorporated by reference herein to describe the state of the art to which this invention pertains. Full citations of the references appear at the end of the specification.
Protein-nucleic acid interactions are involved in many cellular functions such as transcription, RNA splicing, and translation. Small peptides with unnatural backbones that can bind with high affinity to a specific sequence or structure of nucleic acids and interfere with protein-nucleic acid interactions would provide useful tools in molecular biology and medicine. Recently, minor-groove-binding polyamide ligands have been designed for sequence-specific recognition of DNA.1 In contrast to DNA, RNA molecules can fold into extensive structures containing regions of double-stranded duplex, hairpins, internal loops, bulged bases and pseudo-knotted structures.2 The complexity of RNA structure makes it difficult to design ligands for sequence-specific RNA-recognition. Three-dimensional structures of RNA create binding sites for specific interactions with proteins.
One example of such interactions is the mechanism of trans-activation of human immunodeficiency virus type 1 (HIV-1) gene expression that requires the interaction of Tat protein with the trans-activation responsive region (TAR) RNA, a 59-base stem-loop structure located at the 5′-end of all nascent HIV-1 transcripts.3 Replication of human immunodeficiency virus type 1 (HIV-1) requires specific interactions of Tat protein with the TAR RNA. Inhibition of Tat-TAR interactions is a potential approach for anti-HIV therapeutics. Since structural information is now available for TAR RNA and TAR-Tat peptide complexes from NMR4, photocrosslinking,5 and affinity cleaving studies,6 it is possible to design small molecules to interfere with Tat-TAR function. We have recently begun to examine TAR RNA recognition by unnatural biopolymers.7 